By Rebecca Bowers

EXECUTIVE SUMMARY

In a recently released study, Centers for Disease Control and Prevention (CDC) researchers report that while 81% of patients diagnosed with gonorrhea were treated using dual therapy, nearly one in five were treated with a different regimen.

  • Gonorrhea has progressively developed resistance to most antimicrobials used to treat the infection; as a result, the CDC recommends a dual regimen of ceftriaxone and azithromycin for treatment.
  • Researchers have identified mutations of Neisseria gonorrhoeae that enable ceftriaxone resistance. These mutations may lead to the spread of ceftriaxone-resistant strains globally.

Gonorrhea has progressively developed resistance to most antimicrobials used to treat the infection; as a result, the Centers for Disease Control and Prevention (CDC) recommends a dual regimen of ceftriaxone and azithromycin for treatment. In a recently released study, CDC researchers report that while 81% of patients diagnosed with gonorrhea were treated using dual therapy, nearly one in five were treated with a different regimen.1

Gonorrhea is the second most common notifiable disease in the United States. In 2016, 468,514 cases were reported to state and local health departments, an increase of 18.5% from 2015 figures.2 Neisseria gonorrhoeae, the bacterium that causes gonorrhea, has developed resistance to each of the antimicrobials used for treatment, challenging public health officials. (Contraceptive Technology Update reported on the situation; see the January 2017 article, “STDs at Unprecedented High in United States,” available at http://bit.ly/2hrYtkh.)

To check adherence to the current CDC recommendations for uncomplicated gonorrhea treatment, researchers looked at data collected on a random sample of reported cases of gonorrhea in seven jurisdictions participating in the STD Surveillance Network. They estimated the proportion of patients who received the approved regimen, analyzing patient characteristics and diagnosing facility type.

Although the majority of reported patients with gonorrhea (81%) received the recommended regimen, health officials express concern for those not getting the dual therapy regimen. In the majority of cases treated with other regimens, patients were treated with monotherapy, including 3% of all cases treated with azithromycin only.

“Gonorrhea should not be treated with azithromycin alone,” says Gail Bolan, MD, director of the CDC’s Division of Sexually Transmitted Disease Prevention. “Doing so may accelerate emerging resistance and increase the possibility that the patient may not be cured of their infection.”

The current article’s findings indicate that STD and reproductive health clinics are providing quality care, noted Bolan in a “Dear Colleague” letter. Patients who were diagnosed in these healthcare settings were the most likely to receive the recommended regimen (91% and 94%, respectively), compared to 80% in other healthcare settings, she noted.

Mutations May Be Key

Researchers at the University of North Carolina at Chapel Hill (UNC) School of Medicine have identified mutations in Neisseria gonorrhoeae that enable ceftriaxone resistance. These mutations may lead to the spread of ceftriaxone-resistant strains globally.3

“The first step in stopping a drug-resistant bacterium is figuring out how it becomes resistant to antibiotics that once were able to kill it,” notes Robert Nicholas, PhD, professor and vice chair of UNC’s Department of Pharmacology. “Our results give us clues to how ceftriaxone-resistant gonorrhea is emerging, why this is such a looming problem, and what to focus on to limit it.”

Although N. gonorrhoeae has not yet developed wide resistance to ceftriaxone, the isolates H041 and F89 have been found to be resistant to the medication.4 If ceftriaxone-resistant gonorrhea should spread, gonorrhea would become much more difficult, if not impossible, to treat.

Nicholas and colleagues collaborated with researchers in the laboratory of Ann Jerse, PhD, at the Pentagon’s Uniformed Services University, to demonstrate that ceftriaxone resistance mutations in HO41 and F89 impair the bacteria’s growth rate. Then the researchers conducted laboratory experiments to illustrate that strains with resistance were outcompeted by a non-resistant strain of N. gonorrhoeae, resulting in a diminished amount of resistant bacteria compared to the standard strain.

The investigators infected mice with a mixture of equal amounts of the non-resistant reference strain and the ceftriaxone-resistant, growth-impaired strain. They found that some of the resistant strains rapidly developed higher growth rates and began to out-compete the quick-growing reference strain. This development led researchers to suspect that such bacteria had acquired mutations that improved their growth in spite of the growth-inhibiting effect of the mutations.

Nicholas and his colleagues then focused on one of the mutations that affects a bacterial enzyme, AcnB. The enzyme is known to play an important part in the energy production that powers growth of bacteria. Analysis indicates that the mutant form of the enzyme changes the metabolism of energy of N. gonorrhoeae and causes extensive alterations in the expression of bacterial genes.

The researchers are now looking at how mutant AcnB increases N. gonorrhoeae growth and what other mutations that restore growth may exist in the superbug strains evolved in the lab.

REFERENCES

  1. Weston EJ, Workowski K, Torrone E, et al. Adherence to CDC recommendations for the treatment of uncomplicated gonorrhea — STD Surveillance Network, United States, 2016. MMWR Morb Mortal Wkly Rep 2018;67:473-476.
  2. CDC. Sexually Transmitted Diseases Surveillance, 2016. Atlanta; US Department of Health and Human Services, 2017.
  3. Vincent LR, Kerr SR, Tan Y, et al. In vivo-selected compensatory mutations restore the fitness cost of mosaic penAa alleles that confer ceftriaxone resistance in Neisseria gonorrhoeae. MBio 2018; doi: 10.1128/mBio.01905-17.
  4. Katz AR, Komeya AY, Tomas J, et al. Cluster of Neisseria gonorrhoeae isolates with high-level azithromycin resistance and decreased ceftriaxone susceptibility. Presented at the 2016 National STD Prevention Conference. Atlanta; September 2016.